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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Novel progesterone receptor modulators with gene selective and context-dependent partial agonism
Thomas J Berrodin1, Scott A Jelinsky, Nilsa Graciani
1Women's Health & Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19101-2528, USA.
Biochemical Pharmacology
|November 18, 2008
Summary
Novel progesterone receptor (PR) modulators show selective gene activation, offering potential for improved women's health therapies. These compounds demonstrate a unique gene-selective profile, not a global isoform-selective one, paving the way for targeted treatments.
Area of Science:
- Endocrinology
- Molecular Pharmacology
- Women's Health
Background:
- Progesterone receptor (PR) modulators are crucial for contraception, hormone therapy, and treating reproductive disorders like uterine fibroids and endometriosis.
- Developing tissue-selective PR modulators (SPRMs) is a significant unmet need in women's health, aiming to reduce side effects and enhance efficacy.
- Focusing on the PR-A and PR-B isoforms offers a potential strategy for achieving selective modulation, as they exhibit distinct and overlapping functions.
Purpose of the Study:
- To identify and characterize novel PR modulators with potential tissue-selective activity.
- To investigate the isoform-selective and gene-selective profiles of a novel chemical series, piperazine carbimidothioic acid esters (PCEs).
- To elucidate the mechanism underlying the partial agonism of these novel compounds.
Main Methods:
- Identification of 4-(4-chlorophenyl)-substituted piperazine carbimidothioic acid esters (PCEs) with partial PR agonist activity.
- In vitro assays including T47D cell-based gene activation studies and full microarray analysis.
- Multiplexed peptide interaction profiling and co-activator recruitment assays to explore the mechanism of action.
Main Results:
- The identified PCEs selectively activated some PR-A isoform-regulated genes in T47D cells.
- Microarray analysis revealed a unique gene-selective profile for PCEs, distinct from steroidal progestins, rather than a global PR-A or PR-B isoform-selective profile.
- Partial agonism mechanism was partly dependent on co-activator recruitment but significantly influenced by cell and promoter context.
Conclusions:
- Novel PCEs exhibit a gene-selective modulation profile, suggesting a new approach to PR modulation.
- The mechanism of partial agonism is complex, involving context-dependent interactions beyond simple co-activator recruitment.
- These findings provide a foundation for developing novel SPRMs with potentially improved therapeutic profiles for women's health conditions.
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